← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 124: AML Series, Pt 10 - Allogeneic transplant for AML
Ronak Mistry, Vivek Patel, Dan Hausrath
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Transcript33 lines
- [00:00]
A
Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy. Welcome to another episode of the Fellow on Call, the Hemong Podcast. We're coming at you from Merlot University Medical Center. I'm Ronak.
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B
I'm Vivek.
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C
And I'm Dan.
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A
And in today's episode, we continue on our AML transplant discussion with Dr. Amer Kelker from the Dana Farber Cancer Institute. This is the second part of our two part discussion and once again, I hope our listeners are ready to be blown away with a bunch of pearls of wisdom from Ummer himself.
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B
Remember to check out the website. Can't harp it enough. We spent a lot of time and got some good content there. Really summarize these episodes. Hope you guys enjoy this one.
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C
And you know, as a quick caveat to really this one and last week's episode, keep in mind that we're recording this just before and kind of right around the time that all the abstracts for ASH are starting to drop. And so there's a chance that there might be some groundbreaking new thing. Hopefully there will be in the transplant world that we don't talk about. That's the reason why it's not like we're not paying attention. It's just unfortunately, the nature of recording these podcasts. We have to do them a little ahead of time before they're released. So always stay tuned to ASH and the abstracts that come out. Stay on that social media to find out when things are coming. But that's one important caveat I just wanted to mention.
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A
But that's the fun part about hematology and oncology is that it's always changing and we just try to do better and better each and every day. So certainly something to be proud of for sure. And that should encourage you all to make sure you check out ASH abstracts as soon as they drop, whether you're attending the meeting or not. So anyway, guys, that's just our two cents. Let's go ahead and roll. That's. That was an awesome discussion. And, you know, moving this conversation along. We are now presenting this patient with this conditioning regimen and there were all these discussions being had about doing a myeloablative conditioning regimen. Albert, can you tell us what this really means? And we also sometimes hear about reduced intensity conditioning or RIC approaches. What is that? And what sorts of patient demographics are we considering that in.
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D
Yeah, so myeloablated and reduced intensity mainly have to do with the dose of the treatment. So typically if you think about like one of the classic regimens like fludarabine and busulfan or Flubu, Flubu 4 is considered a myeloidative regimen compared to Flubu 2 which is considered a reduced intensity regimen. You can do similar things with doses of TBI for TBI based regimens and then there are other group but the vast majority of treatments or I should say vast majority regimens that we think about follow us on a spectrum. And there's a, there's a really nice blood paper from about 10 years ago that kind of show that spectrum and where the cutoff is for myeloblative and reduced intensity. As for how you choose the difference of the two, again there's actually a good trial or actually three trials that really looked at this quite nicely. There was BMT CTN 0901, that was a US study. There's the European BMT Society's study, Rick Mac and then there was a German AML study as well. Now these studies had different outcomes. I think it's important to understand why. So BMT CTN on Diana 1 looked at patients 18 to 65 years old. They found lower transplant related mortality with reduced intensity conditioning that was imbalanced with higher relapse from those reduced intensity transplants, ultimately yielding higher overall survival for patients that got myeloblade transplants at both 18 months which was the primary endpoint. And then later on for the long term follow up that survival difference was maintained. However, with the Rick Mack and German AML study they didn't see difference between these. And again this was 18 to 60 or 65 years old myeloid malignancy groups. But the important differences was that the European studies, Both EBMT and EBMT's RC Mac and the German study powered their studies for transplant early mortality, not for overall survival. And the RCMAP study actually ended up closing his accrual a little bit early. So I tend to rely more on 0901 than those studies when kind of thinking about this. And so that's why generally for myeloma malignancy, for especially younger patients, and Certainly up to 60 or even 65 will favor myeloablative transplants for patients that are in the 60 to 65 range or even older, the data doesn't quite bear out as favorably for those patients getting myeloablative transplants. And that NRM starts to go up. And so you start to lose the net benefit from the graft versus leukemia effects. And so for those patients, it starts to go down. And then for diseases that are not myeloid diseases, where we don't tend to see as much graft versus leukemia effect or don't have leukemia, like say myelofibrosis, we tend to favor less chemo is better, you know, is potential less harm. You want a sufficient dose to clear the marrow or in a sense to allow for the transplant to not be rejected. But you don't want to give too much chemo that ends up causing additional harm. And we know certainly that more chemo tends to be associated with higher risk for, you know, occlusive disease, for GVHD and other transplant related morbidities and mortality.
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B
Yeah, that was so interesting to me. Cause I always wondered, you know, if honestly I didn't really look into the randomized data between this stuff. And it's another good point for our listeners. When you think about surrogate endpoints, when you really the goal here is overall survival, of course treatment related mortality is going to be better if you use less chemo. I mean, that kind of seems to be common sense. So it's very important when you look at these studies to know what was their primary endpoint and are they powered? Are you going to get a false negative result? An underpowered study, you run that risk of getting a false negative result that actually could be a difference in overall survival. So that's really, really critically important. One of the things that you had mentioned when it comes to these conditioning regimens was tbi. And just from somebody who knows nothing about this idea of total body irradiation thing, what exactly is that and is it just certain protocols call for it? What is tbi?
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D
Yeah, so TBI actually is one of the original regimens. When you think back to early days of transplant and even pre transplant era, when we were first learning about leukemia, we learned that total body radiation could theoretically cure leukemia, but was too toxic. And so that's where it was held back. And we didn't really become a biobank treatment until we really learned how to do the transplants successfully in the 70s and beyond total bodily radiation, you know, you're exposing patients to a certain dose of radiation that does have that ablative or at least effect of allowing for new marrow to come in and replace the existing marrow. And generally TBI based regimens tend to have the lowest rates of graft rejections. And so it is kind of one of those tools that will use higher risk groups for graft rejections like sickle cell disease, if we're going to use a reduced intensity transplant as opposed to an ablative transplant, we found that adding TBI to those regimens can often reduce the risk of graft rejections.
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A
Yeah.
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C
And that's just, you know, they've been exposed to a variety of blood transfusions and folks with chronic anemias and, and so lots of antigen sensitization. That's kind of the thought there's.
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D
Exactly. And one, I think speaking of sickle cell disease is near and dear to my heart. One additional note. So usually for not like Ed mentioned, the general dogma is that for non malignant diseases that we tend to prefer doing reduced intensity transplants. And part of the reason for that is obviously there's more nrm, you don't really get the GDL benefits. But also one of the things that these studies also looked at, because there was a, there was a big concern about it was secondary malignancies in BRIC Mac and in CTN and OMA1 and the German trial, we didn't see any differences or really high amounts of secondary malignancies. That's not the case for a patient with sickle cell disease who seem to have a disease of chronic marrow inflammation in some sense. And so for those patients, I don't know if this is an AML kind of focused series, but since we're talking about transplant, I wanted to at least flag this, that for those patients we do see a lot of secondary malignancies, particularly those that get non myeloablative or reduced intensity regimens. And so for those patients, I think that has been the standard. And so you can use things like TBI to try and correct this. But at our center, actually we do a myeloablative regimen whenever possible for those patients because we found that myeloablation in those patients really does significantly reduce secondary malignancies.
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C
Another important thing we touched on during our discussion of AML is the role of MRD testing. And I think you referenced that even earlier in this podcast. So let's say this patient was MRD positive by FLT3ITD PCR, but was NPM1 negative. How is MRD testing being integrated into our transplant decision making? Is it used to help determine who needs a transplant? Or what about sort of how we use it in surveillance post transplant? What's the role for this in your practice?
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D
Great question. What if we talk about MRD or measurable residual disease testing? I think one of the first things I like to say up front for particularly for myeloid malignancies, is that there isn't really a standard methodology that's used across all centers. So when we talk about this, it is a little bit of a moving target. It's still something that's measured by the cabmtr, which is a national organization that does studies, longitudinal studies in transplant and rate centers and things like that. But when we generally think about it, most centers are talking about MRD by flow cytometry in the case of leukemia in particular. And then this is different for say all. So for lymphoid leukemias, where now we're talking about PCR based test. In the example that you guys have given, we were talking about AML, we were talking about MRD testing. There's actually two groups here. So for npm1, there is a pretty high quality npm1 PCR test that can be used for npm1 specific MRD testing. But then for those patients, we can also still measure the flow test for general AML flow cytometry that might get around, say if there's loss of that particular mutation through transplant or some other means, if it was maybe a subclone and not the primary leukemia, not the driver mutation for the leukemia. So getting through all that kind of mess. The general point is that I personally test mrd. I want to have it before I take a patient transplant. Understanding that patients that are MRD positive are probably higher risk if they don't have transplant. Transplant is considered an equalizer for MRD and specifically for patients that are MRD negative, there have been some studies that show that there aren't differences as much in outcomes between myelombladive and reduced intensity regimens. And so I'm, I'm throwing in a bunch of nuggets here. Cause I, I, it's, it's kind of one of those areas where there's just not a lot of big studies, it's all just individual studies that we've kind of piecemealed together an understanding of how to use this. I think particularly for MRD testing. For Flit 3, with that PCR test, there is a little bit more data. There was a pooled analysis of the APL17 and 19 clinical trials that end up showing that some of it confirmed what we already knew, which is that patients that are MRD positive are at a higher risk group and probably will benefit from transplant, even though that is a favorable risk AML by ELN criteria. But for patients that are MRD negative in that group in that study, they also showed that transplant was really not beneficial, except for a couple patients that may have some secondary mutations that raised their risk class in some way.
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B
So when it comes to some of this stuff, and we've talked in our podcast many times about MRD flow testing, MRD by pcr, MRD NGS testing, there's all these techniques that are coming down the pipeline and it's really, how sensitive do we really need to be? And obviously that's a moving target. And for you, with this FLT3ITD PCR, it sounds like, look, we don't have a standardization here. It might help you choose Rick versus Mac, which makes complete sense, right? If you got an MRD negative patient, maybe you're like, okay, well, let's not blow them up with a myoblative conditioning regimen. So after that, we think about maintenance therapy and we've kind of talked a little bit about this. So can you discuss the role of maintenance therapy post transplant? We had the morpho study, which misses p value barely p value 0.051. And you know, when it comes to these patients, how do you think about continuing on? And before that, we talked about the sormane study and sorafenibs. We've really covered all of this data. So really, for you, when are you incorporating maintenance in the post transplant setting?
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D
Oh, I love that you mentioned more photons for maintenance, because I think those are probably the two most interesting studies in the space. In general, like for transplant series. The concept of maintenance therapy is kind of anathema to kind of our existence. Like, the whole idea is that this is a curative therapy, that we're putting patients through hell in some sense to get them to the other side and be able to move on. And so the idea of giving them more chemo when they don't have a relapse feels really bad. So some transplanters really just don't agree with that philosophically. Obviously with FLT3ITD in particular, that is probably one of the few areas where, as you guys have mentioned, there is some evidence. And so with sormane, it was a positive trial, it was only a phase 2 trial and had a lot of GI toxicity. So even though in theory we should be giving this to patients, I'm very choosy about which patients I give this to. And I definitely have a. It's more of a discussion with the patient about risks and benefits, understanding that it was a small study, but it was a small study that yielded a positive overall survival benefit. I think it was like a 30% difference in camera, I think it was like 18 months survival. It's pretty substantial. So that's really important. Then with morpho, as you guys mentioned, this was a negative study. It just missed the cutoff. This is one of the studies that when the original abstract was released, it was actually looked a lot more alarming. So there was actually worse survival in the treatment group in the initial reporting. And that was kind of freaked a lot of us out who were based on other studies using Giltratinib already for maintenance therapy, off trial. And so it was a gut ship moment. It ended up working out fine. So I think, as you guys mentioned, most of us have fallen into a habit of for patients that are MRD positive or otherwise high risk in some way, we might have a conversation with them about Giltratinib. It's much better tolerated than Serafanin. And so that is one that can be used in that specific area. And again, the specific use of MRD testing for MRD testing for where we can apply this benefit, it's not FLT3ITD MRD testing, but MRD flow.
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A
Just absolutely so interesting. And we've been saying this for what feels like years now. MRD testing is on the brink of becoming something big, but we're just not quite there yet. But it's nice to see some early data starting to show its utility.
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C
I appreciate you going over all that with us. I'm almost hesitant to ask this deep into the podcast, but I'm just too interested. I find this topic a little bit too fascinating. Gvhd. So we've mentioned this a couple of times. Major cause of sort of morbidity and mortality after transplant. And the topic obviously could be a series in itself, a series of podcast episodes at the minimum, an entire podcast all on its own. But very briefly, could you kind of tell us what exactly GBHD is and sort of the main ways it manifests? Am I wrong in thinking that it tends to crop up in these immunological complicated regions where sterile and non sterile sites interface? Like I tend to see GBHD of the skin, eyes, gut, that sort of thing. Just little intro to gvhd, if you could.
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D
Yeah, and I think that's actually a great kind of broad descriptor. I think the important things to when you think about GVHD is that you bucket into two groups. There's acute GVHDs that tend to occur in the first six months, most commonly occurring in the first, I should say from 30 to 90 days, and then usually drops off in incidences after six months. And then there's chronic GVHD syndromes which start around six months and tend to peak close to the one year mark and then drop off pretty quickly. And usually after two or three years, you don't tend to see new chronic GVHD unless you've done something like give someone, give a patient donor lymphocyte infusion as a kind of secondary treatment for relapse or things like that. In terms of organ manifestations, as you mentioned, for acute GVHCs, we're talking about skin, gut, meaning primarily the lower GI tract, but occasionally upper GI as well, manifesting as diarrhea. And then liver GHD primarily with elevated bilirubins, a direct bilirubinemia. And then sometimes you'll see kind of atypical syndromes with elevated transaminases or occasionally other kind of manifestations that are described in the literature much less frequently. But those are the three ones that are used for grading criteria and are very important for chronic gbhd. You're thinking, again, skin, but different skin manifestations. Kind of less often you'll be that kind of red classic hot macropapular itching rash that you'll see in the acute GVHDs. You're going to see more chronic skin changes. You'll often see GVHD in the eyes and mouth. These are, and I think of chronic GVHD as a scarring disease. Acute GVHD is all T cell mediated. Chronic GVHD is both T and B cell mediated, leaning, B cell mediated. And so when you think about chronic scarring, you know, you think of like the lacrimal glands of the eyes, the secretory glands in the mouth that makes saliva. Definitely it's scarred. And as a result you end up with these very, very dry syndrome that's very uncomfortable for patients and leads to a lot of morbidity, even though it doesn't lead to that particular beneficiation, doesn't lead to a lot of mortality. And then the other types that you can see, you can sometimes see like GI tract chronic changes like webbing, or the one that we think of as the worst type of chronic gvhd, which is lung GVHD that's typically presented in the form of bronchiolitis, winteries. So it's an obstructive type of lung disease. And then just very, very briefly, on treatment, you know, historically GHDs were always treated with steroids. There have been three approved GVHD therapies in the last 10 years, where previously we had none. These are all in the second and third line after steroids. So in terms of approvals, we have ibrutinib, which is the first one. This one was proven to be kind of effective at treating chronic gbhd. It's not used very much in practice primarily because the benefits seen in the trial didn't seem to translate a lot into clinical practice. So you don't see it used a lot. Then after that came ruxolitinib and this was seen as beneficial in both acute and chronic gbhd. So that tends to be your second line treatment for most people. And then third line, if you're not looking at a trial, is bellumosidil or resuroc. That was shown to be very beneficial in the Rockstar trial. And there's a bunch of other studies going on. There's CSF1R inhibitors that were shown just recent, as recently as ASH last year to really be significantly improved chronic ghg. And there's a whole host of other treatments that are used off trial or being studied on a trial to have additionally advanced treatments in these areas. There's a group of kind of inhaled and systemic therapies that are used also specifically for lung GVHD that can also be beneficial. And again, as you may just mentioned, there's going to be a whole podcast or series talking about this and there have been. And so I don't want to retrain on that, but just to introduce those concepts to your audience.
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A
These are great reminders for sure, and a nice recap of different options for the board exams for those that are going to take them in the future. So, amar, now it's 2024 and we're at the end of 2024, but nonetheless we have haplotransplants available. Can you tell us a little bit about post transplant cyclophosphamide and the risk of G with haplotransplants?
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D
Yeah, and so this was, I think most of us would consider to be the biggest advancement in transplant of this generation. So, you know, post transplant cyclophosphide has been kind of studied. It was originally explored as a concept in the lab way back, I think as far back as the 80s, and then kind of didn't really reach clinical practice until the late 90s, really the early 2000s, when you start to see the first small trials where it's introduced by the later 2010s, you start seeing really it find a home in haplotransplants and that kind of opening up that avenue of transplant for Folks. And now actually there was a recent trial published in New England Journal, I think it was early 2023 that used post transplant cyclophosphid even for match unrelated donors and even for mass related donors for reduced intensity transplants, showing that that was superior to a calcineurin inhibitor like tacrolimus with methotrexate, which was part of the previous standard of care. So it's really kind of taken the whole field by storm. It's been considered to be a great equalizer for haplotransplants to where we see a much less of a difference in graft versus host disease risk for haplotransplants between that and match unrelated donor transplants. It's we still consider haplotransplants at most centers to be an alternative donor. I think there are some centers that really do treat them totally kind of indistinguishably. But for most, at least our center and I think probably still most centers, you're going to think of match related donors or match sibling donors as your bet, as kind of your first choice donor. Your second choice donor is a matched unrelated donor and then haplo donors and slightly mismatched unrelated donors as kind of equivalent. And they're if you go to ASTCT meetings, there are debates I feel like every year about what is the current data and paradigm and most people will use those. And for me personally, I don't want to speak for others. I kind of treat haplotransplant and mismatched unrelated donor like a seven out of eight as equivalent and then really use things like age and other factors that are patient specific and donor specific as the timer occurs there.
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B
One question about haplotransplant before we wrap up this episode and I think Dan and Ronick have thought of a really good important question to end on of a paper you just published actually. But last thing on haplotransplant, what's the age cutoff? Let's say you have a dad and one of the kids might be a half batch or something like that. What's the age cutoff for a haplotransplant?
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D
Yeah, and I think we at least at Dana Farber, I don't want to speak in every other center because I think there is a lot of heterogeneity here. But generally we use somewhere in the 60 to 65 range as an uppercut for all donors as that will include everything from haplo donors to match sibling donors. So, you know, I think that is kind of the upper point, at which point you start increasing risk for secondary malignancies, donor derived, I should say secondary malignancies. And so that's kind of where we kind of draw the line. Generally most of the time when you're talking about haploid donors in the adult setting, you're almost always talking about kids or siblings or nephews or nieces or cousins or things like that. I can think of for myself only one case that I've had where we've used a parent for half blood transplant. I'm sure other transplant centers to pediatric patients or AMIA patients are going to do that more often. But generally in the adult transplant setting you're going to be thinking about kids. And so generally you get a younger donor as the result.
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A
So we have one question that we thought would be a good question to end on. And as we are aware, and as many of our listeners are probably aware, there have long really been racial disparities when it comes to transplant outcomes. And as Vivek alluded to, we saw that you and some collaborators recently published an article that suggested that there are improvements in allo and auto transplants in racial minorities, which is certainly reassuring based on everything that we had learned prior. But we are curious what are some of these factors that have contributed to these disparities? And I think the important question is what steps are being taken to address.
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D
A lot of these. Yeah, I was glad that the CMMDR was willing to take this issue on as a paper. I think that unfortunately, just like how there are smaller populations of each kind of different ethnic and racial minority other than white patients, there are also fewer donors for those populations. I think that this kind of where the problem initially stems, but also if you look at the distribution of where a lot of racial and ethnic minorities are outside of the ones that are kind of centered in cities, they may not have access to transplant centers quite as easily either due to geographic or insurance based kind of access disparities. And then there's issues related to other socioeconomic barriers. The reason I'm, I'm hedging a little bit here is that one of the things that when we tried to, you know, in the study, we saw that there were large differences that the gaps were closing a little bit in terms of racial disparities, with the exception of non Hispanic black patients, where their outcomes are still significantly worse with transplant compared to other racial ethnic minorities or white patients. And so that is a major gap that needs to be addressed. Some of the things that we are trying to do to correct this. So we're trying to work on expanding our donor databases. More and more countries are developing donor databases. So we're getting more and more international options as well. There's, I think, a, a larger push to address some of the issues that come with implicit biases that may cause us to treat patients differently. Maybe kind of rule them out for various reasons for transplant a little bit more easily that might have happened along the way. Not that I'm pointing fingers at anyone, but saying that I think this is an issue across medicine we're working to address. And then there's things like addressing things like clinical trial diversity that might help close these gaps as well. I know AKSH has a big push on this and there's a lot of research groups looking at trying to fix this issue as well. So I think still a lot to learn about where the issues are, but more importantly, I think starting to try and pivot towards creating more equitable access to transplant and kind of making sure that we're addressing pointing resources to patients that may need more resources. And this is both for racial and ethnic minorities as well as people with other challenges like lack of caregiver support, like I mentioned earlier, or other things. All these are areas where I think as we get better at targeting our resources and develop more resources for these patients, I think we'll start to close those gaps.
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C
Awesome. Thank you so much for talking about that. I think it's such an important issue and it's one of these things that it's just going to improve outcomes across the board. We need to get better. I'm glad that you're thinking about it and also just thank you for being so generous with your time while you're out on parental leave and coming to talk with us again. We love our discussions with you. So this has been another great one.
- [25:20]
D
This is a lot of fun. Thanks for having me on. Hopefully people found this interesting and it wasn't just me talking to you guys for an hour.
- [25:28]
B
No, this is absolutely excellent and our listeners are going to love this. This is going to be a two part episode so we split it into two. And it's so many important things on this episode. It's going to allow us to make really good show notes. Actually we're going to check out our show notes for just the high level pearls from this. There's so many things that I've learned today as a malignant hematologist, I didn't know a lot of this stuff. So thank you so much for taking your time to do this.
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D
My pleasure. And keep doing what you're doing. Love the show.
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A
Thanks, Amar. We appreciate you being here. So until next time, listeners. We'll see you all later.
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B
See you later.
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C
Peace.